EP0302372A1 - Antianaerobe Naphthyridinverbindungen - Google Patents
Antianaerobe Naphthyridinverbindungen Download PDFInfo
- Publication number
- EP0302372A1 EP0302372A1 EP88112104A EP88112104A EP0302372A1 EP 0302372 A1 EP0302372 A1 EP 0302372A1 EP 88112104 A EP88112104 A EP 88112104A EP 88112104 A EP88112104 A EP 88112104A EP 0302372 A1 EP0302372 A1 EP 0302372A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- naphthyridine
- compounds
- fluoro
- dihydro
- oxo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- This invention relates to new use of naphthyridine derivatives. These derivatives have antibacterial properties and particularly unexpected and superior anti-anaerobic properties.
- naphthyridine compounds exhibit antibacterial properties, most notably Enoxacin which is an 1-ethyl-6-fluoro-1,4-dihydro-4-oxo 7-piperazin-1-yl,8-naphthyridine-3-carboxylic acid.
- Enoxacin is an 1-ethyl-6-fluoro-1,4-dihydro-4-oxo 7-piperazin-1-yl,8-naphthyridine-3-carboxylic acid.
- this compound and other quinoline analogs are not very effective against anearobic organisms.
- This invention relates to 7-substituted -pyrrolidin-1-yl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids and derivatives thereof having the formula: wherein R1 is hydrogen or a carboxy-protecting group; and pharmaceutically acceptable salts thereof.
- carboxy-protecting group refers to a carboxy group which has been esterified with one of the commonly used carboxylic acid protecting ester groups employed to block or protect the carboxylic acid functionality while reactions involving other functional sites of the compound are carried out.
- a carboxy protecting group can be used as a prodrug whereby the carboxy protecting group can be hydrolyzed enzymatically to release the biologically active parent acid.
- Such protected carboxy groups are noted for their ease of cleavage by hydrolytic methods to the corresponding carboxylic acid. Further, such carboxy-protecting groups can be relatively easily cleaved to yield the corresponding free carboxy group.
- Such carboxy-protecting groups are well known to those skilled in the art, having been extensively used in the protection of carboxyl groups in the penicillin and cephalosporin fields, as described in U.S. Patent Nos. 3,840,556 and 3,719,667, the disclosures of which are incorporated herein by reference.
- Representative protecting groups include C1 to C8 alkyl (e.g., methyl, ethyl, tertiary butyl), benzyl and substituted derivatives thereof such as alkoxy and nitrobenzyl groups, dialkylaminoalkyl (e.g. dimethylaminoethyl), acyloxyalkyl groups such as pivaloyloxymethyl and propionyloxy methyl.
- the chiral centers of the compounds of the invention may have either the "R” or "S” configuration.
- pharmaceutically acceptable salts of the foregoing compounds.
- pharmaceutically acceptable salts refers to non-toxic acid addition salts and alkaline earth metal salts of the compounds of formula I.
- the salts can be prepared in situ during the final isolation and purification of the compounds of formula I, or separately by reacting the free base or acid functions with a suitable organic acid or base.
- Representative acid addition salts include the hydrochloride, hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, glucoheptonate, lactobionate, lauryl sulfate salts and the like.
- Representative alkali or alkaline earth metal salts include the sodium, calcium, potassium and magnesium salts, etc.
- the compounds of the present invention possess antibacterial activity against a wide spectrum of gram positive and gram negative bacteria, as well as enterobacteria.
- the compounds of the invention are therefor useful in the antibiotic treatment of susceptible bacterial infections in both humans and animals.
- the compounds by reason of their in vitro activity, may be used in scrub solutions for surface inhibition of bacterial growth.
- Representative of the preferred compounds of the invention include 1-o,p-difluorophenyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-aminopyrrolidin-1-yl)-1,8-naphthyridine -3-carboxylic acid hydrochloride, 1-o,p-difluorophenyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-aminopyrrolidin-1-yl)-1,8-naphthyridine-3-carboxylic acid sulfate, 1-o,p-difluorophenyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-aminopyrrolidin-1-yl)-1,8-naphthyridine-3-carboxylic acid tosylate.
- Susceptible organisms generally include those gram positive and gram negative, aerobic and anaerobic organisms whose growth can be inhibited by the compounds of the invention such as Staphylococcus , Lactobacillus , Streptococcus , Sarcina , Escherichia , Enterobacter , Klebsiella , Pseudomonas , Acinetobacter , Proteus , Campylobacter , Citrobacter , Nisseria , Baccillus , Bacteroides , Peptococcus , Clostridium , Salmonella , Shigella , Serratia , Haemophilus , Brucella , and other organisms.
- Anaerobic organisms are susceptible to the compounds of formula I and include Bacteroides fragilis , other Bacteroides species, Fusobacterium nucleatum , other Fusobacterium species, Veillonella , parvula , Clostridium difficile , Clostridium perfringen , other Clostridium species, peptococci and peptostreptococci and Propionibacterium acnes .
- the compounds of formula I may also be formulated into compositions together with pharmaceutically acceptable carriers for parenteral injection, for oral administration in solid or liquid form, for rectal administration, and the like.
- compositions according to the invention for parenteral injection may comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, suspensions or emulsions.
- suitable nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils, such as olive oil, and injectable organic esters such as ethyl oleate.
- Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents into the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
- Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
- the active compound is admixed with at least one inert diluent such as sucrose, lactose or starch.
- Such dosage forms can also comprise, as is normal practice, additional substances other than diluents, e.g., lubricating agents such as magnesium stearate.
- the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixers containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
- compositions for rectal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as cocoa butter or a suppository wax.
- Actual dosage levels of active ingredient in the compositions of the invention may be varied so as to obtain an amount of active ingredient effective to achieve antibacterial activity in accordance with the desired method of administration.
- the selected dosage level therefore depends upon the nature of the active compound administered, the route of administration, the desired duration of treatment and other factors.
- daily dosage levels of the compounds of Formula I of about 0.1 to about 750, more preferably about 0.25 to about 250 and most preferably about 0.5 to about 30 mg. of active ingredient per kg. of body weight are effective when administered orally to a mammalian patient suffering from an injection caused by a susceptible organism.
- the daily dose may be divided into multiple doses for administration, e.g., two to four times per day.
- Ethyl 2,6-dichloro-5-fluoronicotinate (20 g, 84 mmol) was dissolved in a mixture of 40 mL of trifluoroacetic acid and 40 mL of 7.5 N HCI. The mixture was heated to reflux for 24 hours. The solution was cooled, and the trifluoroacetic acid was removed by evaporation under reduced pressure. Upon cooling, 100 mL of water was added and a white precipitate formed. The precipitate was filtered, washed with hexane, and dried, yielding 12.91 g (73.2%) of 2,6-dichloro-5-fluoronicotinic acid: mp 153-154°C.
- 2,6-Dichloro-5-fluoronicotinic acid (7 g, 33.3 mmol) was dissolved in thionyl chloride (35 mL). After the mixture was heated at 80°C for 2 h, the thionyl chloride was removed by evaporation under reduced pressure yielding a yellowish 2,6-dichloro-5-fluoronicotinyl chloride.
- Monoethyl malonate (13.2 g, 100 mmol) and 3 mg of biquinoline was dissolved in 280 mL of dry tetrahydrofuran (THF) and cooled to -30°C.
- Example 2 2.5 g of the product of Example 1 was dissolved in 17 ml of 1 N sodium hydroxide solution. Water (60 ml) was added and then followed by the addition of acetic acid (0.7 ml). The precipitate was filtered and washed with water yielding 2.2 g of 1-o,p-difluorophenyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-aminopyrrolidinyl-1-yl)-1,8-naphthyridine-3-carboxylic acid (96%).
- Example 2 To a suspension of product of Example 2 (404 mg, 1 mmol) in water (35 ml) was added in 1 ml 1 N sulfuric acid solution. The mixture was warm to dissolve and evaporated under reduced pressure to dryness to give the sulfate salt of Example 2 (430 mg).
- IR (HBr) cm ⁇ 1; CO 1725 NMR (DMSO-D6); delta value 2.01 (1H, m), 2.19 (1H, m), 3.26-3.86 (5H, m), 4.01 (1H, m), 7.36 (1H, m), 7.60 (1H, m), 7.81 (1H, m), 8.15 (1H, d, J 13 Hz), 8.85 (1H, s),
- Example 2 A suspension of 1.02 g of Example 2 and 480 mg of p-toluenesulfonic acid monohydrate in 100 ml of water was heated to boiling until it became a solution. The solution was then cooled to room temperature and the product was then freeze dried to yield the tosylate salt of Example 2 (1.40 g).
- Example 2 To a suspension of product of Example 2 (404 mg) in water (40 ml) was added in 97 mg of methanesulfonic acid. The mixture was warm to dissolve and the solution was freeze dried to give the methanesulfonate salt of Example 2 (500 mg).
- IR (KBr) cm ⁇ 1; CO 1725 NMR (DMSO-D6); delta value 2.03 (1H, s), 2.20 (1H, m), 2.30 (3H, s), 3.21-3.82 (5H, m), 7.35 (1H, m), 7.58 (1H, m), 7.83 (1H, m), 7.95 (2H, m), 8.15 (1H, d, J 13 Hz), 8.84 (1H, s).
- the drying agent was removed by filtration and the solvent was removed on a rotary evaporator giving 860 mg (87%) of a clear colorless oil.
- the oil was dissolved in 5ml of dry benzene and was placed in an oven-dried flask protected from moisture. To this was added 555 ml (5.0 mmol) of acetic anhydride in 2 ml of dry benzene.
- the reaction mixture was stirred at room temperature for 20 h.
- the reaction mixture was neutralized with 0.5N NaOH.
- the aqueous layer was extracted with CH2Cl2, 3 x 20 ml.
- the combined organic layers were dried over Na2SO4.
- the solution was filtered and the solvent was removed on a rotary evaporator.
- the in vitro antibacterial activity of the test compound was determined by conventional agar dilution procedures.
- the organisms were grown overnight in brain-heart infusion (BHI) broth (Difco 0037-01-6) at 36° C.
- BHI brain-heart infusion
- Twofold dilutions of the stock solution (2000 mcg/mL) of the test compound were made in BHI agar to obtain a test concentration ranging from 200 to 0.005 mcg/mL.
- the plate was inoculated with approximately 104 organisms. It was then incubated at 36°C for 18 h.
- the minimal inhibitory concentration was the lowest concentration of the test compound that yielded no visible growth on the plate.
- Example 1 The results of in vitro testing of Example 1 are shown in Tables I and II below: Table I In-Vitro Test for Compound of Example 1 Organism MIC ( mcg/ml) Staphylococcus aureus ATCC 6538P .05 Staphylococcus aureus CMX 686B .05 Staphylococcus aureus A5177 .1 Staphylococcus aureus 45 .1 Staphylococcus aureus 45 RAR2 .1 Staphylococcus epidermidis 3519 .1 Staphylococcus epidermidis 3519 RAR1 .1 Lactobacillus casei ATCC 7469 .2 Streptococcus faecium ATCC 8043 .2 Streptococcus bovis A5169 .78 Streptococcus agalactiae CMX 508 .39 Streptococcus pyogenes EES61 .2 Micrococcus
- B. fragilis (ATCC25285) was passaged three times in connective tissue air pouches of mice (CF-1 female mice weighing 20 g obtained from Charles River Breeding Laboratories, North Wilmington, MA), in order to obtain a virulent organism which consistently yielded viable counts greater than 105 cfu in the air pouch over a seven day period. This culture was maintained frozen at -60°C. An 18 h culture of the passaged virulent B.fragilis in thioglycollate broth was diluted 1:2 in physiological saline. 0.5 ml portion of this diluted culture was used to inject the air pouches of mice.
- Air pouches were made on the dorsum by the injection of 2-5 ml of air into subcutaneous tissue of mice as described by Clark & Weinhold, Journal of Medical Microbiology 12, 233-7, 1979. The inoculum was then injected directly into the air pouch.
- mice were treated subcutaneously. Groups of five mice were treated with at least three different doses of each of the test compounds. The drugs were administered 1 h after infection and followed by twice a day treatment for 4 days. The daily doses were administered 8 h apart. Five mice were left untreated to be used as controls.
- Table III Numbers of viable Bacteroides fragilis isolated from abscesses Log CFUs (+SEM) Dose (mg/kg)
- Table III Ciprofloxacin Metronidazole Untreated control 0 3.4 ( ⁇ 0.16) 3.1 3.7 ( ⁇ 0.5) 4.0 ( ⁇ 0.1) 3.8 ( ⁇ 0.2) 12.5 2.7 ( ⁇ 0.5) 3.6 ( ⁇ 0.2) 3.4 ( ⁇ 0.1) 50.0 0 ( ⁇ 0.0) 2.4 ( ⁇ 0.2) 2.0 ( ⁇ 0.2)
- Example 3 As can be seen from Table III, the compound of Example 3 is 4 times more active than ciproflaxacin (another quinoline antibacterial) and 3-4 times more active than metronidazole against Bacteroides fragilis ATCC 25285. Metronidazole is a clinically useful antibacterial agent which is recommended for treatment of B. fragilis infections in man.
- Example 3 cleared the infection in all abscesses when treated with 50 mg/kg, whereas in ciprofloxacin treated animals 2.4 ( ⁇ 0.5) log CFUs were found in the abscesses, and in metronidazole treated animals 2.0 (+0.2) log CFUs were found in the abscesses.
- the compounds of formula 1 are more active than ciprofloxacin and metronidazole. Since metronidazole is considered to be a very effective anti-anaerobic agent and the above tests show the compounds of formula I to be more effective than metronidazole, the compounds of formula I is considered an exceptionally effective anti-anaerobic agent in vivo .
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT88112104T ATE83377T1 (de) | 1987-08-04 | 1988-07-27 | Antianaerobe naphthyridinverbindungen. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US8141387A | 1987-08-04 | 1987-08-04 | |
US81413 | 1987-08-04 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0302372A1 true EP0302372A1 (de) | 1989-02-08 |
EP0302372B1 EP0302372B1 (de) | 1992-12-16 |
Family
ID=22164001
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP88112104A Expired - Lifetime EP0302372B1 (de) | 1987-08-04 | 1988-07-27 | Antianaerobe Naphthyridinverbindungen |
Country Status (10)
Country | Link |
---|---|
EP (1) | EP0302372B1 (de) |
JP (1) | JP2655691B2 (de) |
KR (1) | KR0133176B1 (de) |
AT (1) | ATE83377T1 (de) |
AU (1) | AU2037088A (de) |
CA (1) | CA1314228C (de) |
DE (1) | DE3876712T2 (de) |
DK (1) | DK175609B1 (de) |
IE (1) | IE62600B1 (de) |
NZ (1) | NZ225659A (de) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0391169A2 (de) * | 1989-04-05 | 1990-10-10 | Bayer Ag | Enantiomerereine 7-(3-Amino-1-pyrrolidinyl)-chinolon-und-naphthyridoncarbonsäuren |
US5300643A (en) * | 1989-10-12 | 1994-04-05 | Bayer Aktiengesellschaft | Quinolonecarboxylic acid derivatives |
ES2095809A1 (es) * | 1995-07-27 | 1997-02-16 | Sint Quimica Sa | Procedimiento para la preparacion de acidos naftiridin carboxilicos y sus sales. |
US5739342A (en) * | 1997-03-03 | 1998-04-14 | Abbott Laboratories | Process for the preparation of nicotinic acids |
US6348600B1 (en) | 2001-02-20 | 2002-02-19 | Toray Industries, Inc. | Methods for making optically active 3-aminopyrrolidine-2,5-dione derivative and optically active 3-aminopyrrolidine derivative |
EP1188744A1 (de) * | 2000-08-24 | 2002-03-20 | Mitsubishi Chemical Corporation | Verfahren zur Herstellung von 1h-3-Aminopyrrolidine und Derivate |
EP1236716A1 (de) * | 2001-02-19 | 2002-09-04 | Toray Industries, Inc. | Verfahren zur Herstellung von optisch aktiven 3-Aminopyrrolidin-2,5-dion-derivaten und optisch aktiven 3-Aminopyrrolidin-derivaten |
WO2018220365A1 (en) * | 2017-05-30 | 2018-12-06 | King's College London | Antibiotic resistance breakers |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002284761A (ja) * | 2001-01-17 | 2002-10-03 | Toray Ind Inc | 光学活性3−アミノピロリジン−2,5−ジオン誘導体および光学活性3−アミノピロリジン誘導体の製造方法 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0153580A1 (de) * | 1984-01-26 | 1985-09-04 | Abbott Laboratories | Antibakterielle Naphthyridin- Verbindungen |
DE3514076A1 (de) * | 1984-04-26 | 1985-10-31 | Toyama Chemical Co. Ltd., Tokio/Tokyo | 1,4-dihydro-4-oxonaphthyridin-derivate und salze derselben, verfahren zu ihrer herstellung und antibakterielle mittel mit einem gehalt derselben |
GB2170804A (en) * | 1985-01-23 | 1986-08-13 | Toyama Chemical Co Ltd | Preparation of 1-aryl-1, 4-dehydro-4-oxo-1, 8-naphthyridine and intermediates therefor |
DE3542972A1 (de) * | 1985-12-05 | 1987-06-11 | Merck Patent Gmbh | Pharmakadepot |
JPS6237006B2 (de) * | 1985-10-28 | 1987-08-10 | Toyama Chemical Co Ltd | |
DE3632222A1 (de) * | 1986-09-23 | 1988-04-07 | Bayer Ag | Topisch anwendbare zubereitungen von gyrase-inhibitoren |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6272616A (ja) * | 1985-09-27 | 1987-04-03 | Toyama Chem Co Ltd | 抗菌剤 |
-
1988
- 1988-07-21 IE IE223388A patent/IE62600B1/en not_active IP Right Cessation
- 1988-07-25 CA CA000572917A patent/CA1314228C/en not_active Expired - Lifetime
- 1988-07-27 EP EP88112104A patent/EP0302372B1/de not_active Expired - Lifetime
- 1988-07-27 DE DE8888112104T patent/DE3876712T2/de not_active Expired - Lifetime
- 1988-07-27 AT AT88112104T patent/ATE83377T1/de not_active IP Right Cessation
- 1988-08-02 NZ NZ225659A patent/NZ225659A/xx unknown
- 1988-08-03 AU AU20370/88A patent/AU2037088A/en not_active Abandoned
- 1988-08-03 JP JP63194283A patent/JP2655691B2/ja not_active Expired - Lifetime
- 1988-08-03 KR KR1019880009884A patent/KR0133176B1/ko not_active IP Right Cessation
- 1988-08-04 DK DK198804352A patent/DK175609B1/da not_active IP Right Cessation
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0153580A1 (de) * | 1984-01-26 | 1985-09-04 | Abbott Laboratories | Antibakterielle Naphthyridin- Verbindungen |
DE3514076A1 (de) * | 1984-04-26 | 1985-10-31 | Toyama Chemical Co. Ltd., Tokio/Tokyo | 1,4-dihydro-4-oxonaphthyridin-derivate und salze derselben, verfahren zu ihrer herstellung und antibakterielle mittel mit einem gehalt derselben |
GB2170804A (en) * | 1985-01-23 | 1986-08-13 | Toyama Chemical Co Ltd | Preparation of 1-aryl-1, 4-dehydro-4-oxo-1, 8-naphthyridine and intermediates therefor |
JPS6237006B2 (de) * | 1985-10-28 | 1987-08-10 | Toyama Chemical Co Ltd | |
DE3542972A1 (de) * | 1985-12-05 | 1987-06-11 | Merck Patent Gmbh | Pharmakadepot |
DE3632222A1 (de) * | 1986-09-23 | 1988-04-07 | Bayer Ag | Topisch anwendbare zubereitungen von gyrase-inhibitoren |
Non-Patent Citations (1)
Title |
---|
PATENT ABSTRACTS OF JAPAN, Unexamined Applications, Section C, Vol. 10, No. 328, November 7, 1986 The Patent Office Japanese Government page 154 C 383 * Kokai-No. 61-137 819 (Toyama Chem. Co. Ltd.)* * |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0391169A2 (de) * | 1989-04-05 | 1990-10-10 | Bayer Ag | Enantiomerereine 7-(3-Amino-1-pyrrolidinyl)-chinolon-und-naphthyridoncarbonsäuren |
EP0391169A3 (de) * | 1989-04-05 | 1991-09-18 | Bayer Ag | Enantiomerereine 7-(3-Amino-1-pyrrolidinyl)-chinolon-und-naphthyridoncarbonsäuren |
US5300643A (en) * | 1989-10-12 | 1994-04-05 | Bayer Aktiengesellschaft | Quinolonecarboxylic acid derivatives |
ES2095809A1 (es) * | 1995-07-27 | 1997-02-16 | Sint Quimica Sa | Procedimiento para la preparacion de acidos naftiridin carboxilicos y sus sales. |
US5739342A (en) * | 1997-03-03 | 1998-04-14 | Abbott Laboratories | Process for the preparation of nicotinic acids |
EP1188744A1 (de) * | 2000-08-24 | 2002-03-20 | Mitsubishi Chemical Corporation | Verfahren zur Herstellung von 1h-3-Aminopyrrolidine und Derivate |
US6531594B2 (en) | 2000-08-24 | 2003-03-11 | Mitsubishi Chemical Corporation | Process for producing 1H-3-aminopyrrolidine and derivatives thereof |
EP1236716A1 (de) * | 2001-02-19 | 2002-09-04 | Toray Industries, Inc. | Verfahren zur Herstellung von optisch aktiven 3-Aminopyrrolidin-2,5-dion-derivaten und optisch aktiven 3-Aminopyrrolidin-derivaten |
US6348600B1 (en) | 2001-02-20 | 2002-02-19 | Toray Industries, Inc. | Methods for making optically active 3-aminopyrrolidine-2,5-dione derivative and optically active 3-aminopyrrolidine derivative |
WO2018220365A1 (en) * | 2017-05-30 | 2018-12-06 | King's College London | Antibiotic resistance breakers |
CN110869373A (zh) * | 2017-05-30 | 2020-03-06 | 伦敦皇家学院 | 抗生素抗性破坏剂 |
CN110869373B (zh) * | 2017-05-30 | 2023-03-07 | 伦敦皇家学院 | 抗生素抗性破坏剂 |
US11746116B2 (en) | 2017-05-30 | 2023-09-05 | King's College London | Antibiotic resistance breakers |
Also Published As
Publication number | Publication date |
---|---|
JP2655691B2 (ja) | 1997-09-24 |
IE62600B1 (en) | 1995-02-22 |
DK175609B1 (da) | 2004-12-27 |
CA1314228C (en) | 1993-03-09 |
NZ225659A (en) | 1991-10-25 |
DK435288D0 (da) | 1988-08-04 |
DK435288A (da) | 1989-02-05 |
KR0133176B1 (ko) | 1998-04-17 |
JPH01110626A (ja) | 1989-04-27 |
AU2037088A (en) | 1989-03-02 |
ATE83377T1 (de) | 1993-01-15 |
IE882233L (en) | 1989-02-04 |
EP0302372B1 (de) | 1992-12-16 |
DE3876712D1 (de) | 1993-01-28 |
KR890003378A (ko) | 1989-04-14 |
DE3876712T2 (de) | 1993-05-19 |
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